The increase in the incidence of skin cancer is of great concern. Nearly all deaths caused by skin malignancies result from malignant melanoma. The significant mortality of this disease is caused by the high proliferation rate of melanoma cells and the early occurrence of metastases. The choice of treatment depends on the timely detection of the melanoma and any associated metastases. Although positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG), an 18F-radiolabeled glucose analogue, has been successfully used for melanoma imaging, a 99mTc-labeled single-photon-emission computed tomography (SPECT) radiopharmaceutical with affinity for melanoma may provide a cost effective and more widely available alternative for the same purpose.
Previous attempts to image melanoma with radiolabeled monoclonal antibodies have met with little success. Subsequent use of simpler radiolabeled molecules, including radioiodinated amino acids and nucleic acids as false precursors in the melanin formation cycle either displayed insufficient localization in tumors, and hence low tumor to nontumor ratios, or possessed poor pharmacokinetics. More promising results were recently obtained with 99mTc-labeled α-melanotropin peptides. Tumor uptake and biodistribution studies with these radioconjugates generated favorable results, indicating that labeled peptides may be useful for in-vivo melanoma scintigraphy. The 99mTc-complexes 1-4 have low melanoma uptake of 0.4% to 1.5% (% ID/g, 1 hour post injection) (Auzeloux, P., J. Med. Chem., (2000) 43, pp. 190-199). Nevertheless, the search for non-peptidic, non-immunogenic, small molecules that possess high affinity for melanoma continues.
99mTc-complexes 1-4 and uptake thereof by melanoma cells.
Compound 10.4% uptake Compound 20.7% uptake Compound 31.5% uptake Compound 40.5% uptake
In this regard, melanoma uptake has been obtained with 123I-labeled N-(2-diethylaminoethyl)-4-iodobenzamide ([123I]BZA) and N-(2-diethylaminoethyl)-3-iodo-4-methoxybenzamide ([123I]IMBA). In-vivo investigations with these molecules in C57B16 mice transplanted subcutaneously with B16 melanoma cells showed uptake values ranging from 5% to 9% injected dose/g (ID/g) of tumor. Subsequent human clinical trials also indicated adequate uptake by melanoma and good scintigraphic images. Recent reports have suggested that the uptake is nonsaturable and may be related to the formation of melanin within the melanosome. Although such radioiodinated benzamides have entered phase II clinical trials for the diagnosis of malignant melanoma, their routine clinical use may be hampered by the associated disadvantages of iodine-123, i.e., in-vivo deiodination, lack of routine availability and high cost.
The most widely used isotope in clinical nuclear medicine, technetium-99m, possesses ideal characteristics (t1/2=6.02 h, 140 keV monoenergeric γ-emission) for nuclear medicine imaging and is available on demand from a 99Mo-99mTc generator system. It is desirable to have a small technetium-99m labeled complex possessing high affinity for melanoma. Except for the 99mTc-labeled α-melanotropin peptides, all of the tetradentate 99mTc-complexes that have been published in literature in one form or the other rely on using the benzamides along with the aromatic ring in the overall structure of the complexes. Thus, new and useful 99mTc-labeled diagnostic agents for melanoma imaging are still being sought.